Organocatalysis Enabled by N-Heterocyclic Carbenes

Transcription

1 rganocatalysis Enabled by -eterocyclic Carbenes Acyl Anions X Y omoenolates Acylazolium Azolium enolate Base Catalysis Jiaming Li 2018/04/27

2 tability of -heterocyclic Carbenes 2p x,y,z p π 2p x,y,z p π σ C C σ b 2 2s b 2 a 1.. π-electron donation 2s b 2 a 1 b σ-electron withdrawal a 1 a 1 σ-electron-withdrawing substitutents σ-electron-donating substitutents σ-electron withdrawing substitutents favor the singlet state over the triplet state σ-electron withdrawing substitutents inductively stablize the σ non-bonding orbital by increasing its s character and leaving the p π orbital unchanged σ-electron donating substitutents induce a smaller σ-p π gap, favoring a triplet state Bertrand, Chem. ev. 2000, 100, 39

3 tability of -heterocyclic Carbenes p π p π C σ σ.... π-electron donation a 2 2 p z.. σ-electron withdrawal b 1 π-electron donation The energy of p π orbital is increased by the interaction with the symmetric combination of the substitutent lone pairs. Combined effect is to increase the σ p π gap and stablize the singlet-state carbene over the more reactive triplet-state carbene. Bertrand, Chem. ev. 2000, 100, 39

4 verview Acyl Anions Benzoin condensation tetter reaction ydroacylation omoenolates Annulation Cyclopentene synthesis X Y 2 1 Acylazolium Azolium enolate Claisen rearrangement Cycloaddition Base Catalysis Transesterification Michael addition

5 Benzoin condensation First reported benzoin condensation (Wohler, Liebig, 1832) ac C C 2

6 Benzoin condensation Ugai discovered thiazolium salts could catalyze benzoin condensation (1943) Cl 2 a, Co-enzyme thiamine diphosphate is responsible for the generation of acyl anion P P Pyruvate decarboxylase Pyruvate oxidase Pyruvate dehydrogenase Transketolase 2 thiamine diphosphate (TDP) + C 2 Ugai, T.; Tanaka,.; Dokawa, T. J. arm. oc. Jpn. 1943, 63, 296.

7 Proposed chanism by Breslow Breslow intermediate Breslow,. J. Am. Chem. oc , 80, 3719

8 Enantioselective Benzoin Condensation First asymmetric benzoin condensation catalyzed by chiral thiazolium salts (heehan, 1966) Br * (10 mol%) Et 3 (10 mol%) 9% yield, 22% ee heehan, J. C.; unneman, D.. J. Am. Chem. oc. 1966, 88, 3666

9 Enantioselective Benzoin Condensation Improvement in the enantioselectivity of benzoin condensation cat. C Br Cl 4 6% yield, 52% ee heehan, % yield, 75% ee Enders, 1996 Tf 50% yield, 21% ee Leeper, 1997 TB Cl 45% yield, 80% ee Leeper, 1998

10 Enantioselective Benzoin Condensation Improvement in the enantioselectivity of benzoin condensation cat. C Br 6% yield, 52% ee heehan, 1974 Cl 4 66% yield, 75% ee Enders, aryl-bicyclic triazolium structure Tunable electronics X n 2 1 Tf TB Cl Tunable sterics 50% yield, 21% ee Leeper, % yield, 80% ee Leeper, 1998 BF 4 83% yield, 90% ee Enders, 2002

11 Model Enders, Chem. ev. 2007, 107,

12 Enantioselective Benzoin Condensation ighly efficient system for the enantioselective benzoin reaction (Connon, 2009) Ar 4-8 mol% C 4-8 mol% b 2 C 3 TF, 20 h % Ar Ar BF 4 C 6 F 5 90% yield, >99% ee Cl 91% yield, 92% ee Cl 26% yield, 97% ee Cl Cl 92% yield, 90% ee 17% yield, 43% ee Connon,. J. J. rg. Chem. 2009, 74, 9214

13 Aldehyde-Ketone Cross-Benzoin eaction ynthesis of Bicyclic Tertiary Alcohols 30 mol% cat. 4-8 mol% Cs 2 C 3 C 2 Cl 2, 40 ºC, 24 h 25-90% Cl s 67% yield, >99% ee 37% yield, 94% ee 47% yield, 86% ee 43% yield, 95% ee 50% yield, 78% ee 32% yield, 26% ee akai, rg. Lett. 2009, 11,

14 Aldehyde-Imine Cross-Benzoin eaction Cross Aza-Benzoin eaction with -Boc Imines + Ar Boc 20 mol% cat. CsAc (1 equiv) C 2 Cl 2, 4 Å M, -20 ºC 33-93% Ar Boc BF 4 Cl Cl Et Boc Et Boc Et Boc Cl 83% yield, 96% ee 89% yield, 96% ee 84% yield, 96% ee Boc Boc Boc 86% yield, 84% ee 71% yield, 92% ee 33% yield, 98% ee ovis, Angew. Chem., Int. Ed. 2012, 51,

15 Acyl Anion Equivalent 3 2 benzoin condensation 1 Breslow intermediate

16 Acyl Anion Equivalent 3 2 benzoin condensation 1 Breslow intermediate EWG EWG tetter reaction EWG = C, C 2, C 2, P() 2

17 eminal Works of tetter eaction First general intramolecular tetter reaction catalyzed by C (Ciganek, 1995) C 2 20 mol% cat. Et 3 (1 equiv) DMF, rt 88% C 2 Cl Bn First asymmetric intramolecular tetter reaction (Enders, 1995) C 2 20 mol% cat. K 2 C 3 (1 equiv) TF, rt 73%, 60% ee C 2 Cl 4 Bn Ciganek, ynthesis 1995, Enders, Angew. Chem., Int. Ed. 1995, 34,

18 Improved Asymmetric Intramolecular tetter eaction ighly enantioselective tetter reaction (ovis, 2002) C 2 Et 20 mol% cat. KMD (20 mol%) xylene 94%, 94% ee C 2 Et BF 4 C 2 Et 20 mol% cat. KMD (20 mol%) xylene 81%, 95% ee C 2 Et Bn BF 4 ovis, J. Am. Chem. oc. 2002, 124, 10298

19 Asymmetric Intermolecular tetter eaction Intermolecular tetter reaction with Chalcones (Enders, 2008) Ar 1 10 mol% cat. Cs 2 C 3 (10 mol%) TF + Ar %, 58-78% ee Ar 1 Ar 2 Ar 2 Ar 3 BF 4 Bn TBDP Intermolecular tetter reaction with highly activated alkylidene dicarbonyls (ovis, 2008) Et C 2 t-bu Et 20 mol% cat. ipr 2 Et (1 equiv) Mg 4 CCl 4 C 2 t-bu C 2 t-bu C 2 t-bu 84%, 90% ee Et BF 4 Et %, 92% ee, 5:1 dr Bn C6 F 5 ovis, T. J. Am. Chem. oc. 2008, 130, 14066

20 Asymmetric Intermolecular tetter eaction Intermolecular tetter reaction with nitroalkenes BF 4 C6 F 5 + Cy 2 10 mol% cat. ipr 2 Et (1 equiv) CCl 4, -10 ºC, 12 h Cy 2 90% yield, 88% ee F BF 4 tetter reaction of thyl 2-Acetamidoacrylate C6 F 5 95% yield, 95% ee + elected Examples: Br Ac Ac C 2 C 2 20 mol% cat. 16 mol% K-tBu, rt, 24 h 38-98% 93-99% ee Fe Ac 98%, 96% ee 56%, 99% ee C 2 Ac 8 C 2 Ac 52%, 97% ee C 2 Bn Cl s ovis, J. Am. Chem. oc. 2011, 133, Glorius, Angew. Chem., Int. Ed. 2011, 50,

21 ne-pot ynthesis of Pyrrols and Furans 2 Br + Muller et al. 1. Pd(P 3 ) 2 Cl 2, CuI, Et C, 20 mol% 1 1 i mol% 2 DBU, ipr cheidt et al. 1 Ac Ts I 1 2 Et Br Müller, T. J. J. rg. Lett. 2001, 3, 3297 cheidt, K. A. rg. Lett. 2004, 6, 2465

22 Acyl Anion Equivalent 3 2 benzoin condensation 1 Breslow intermediate EWG EWG tetter reaction EWG = C, C 2, C 2, P() 2

23 ydroacylation 3 2 benzoin condensation 1 Breslow intermediate unactivated alkenes EWG EWG EWG = C, C 2, C 2, P() 2 tetter reaction ydroacylation

24 ydroacylation First hydroacylation precedent (he, 2008) Ts 25 mol% cat. 70 mol% DBU xylene, 4 h = 72% = 82% I

25 ydroacylation First hydroacylation precedent (he, 2008) Ts 25 mol% cat. 70 mol% DBU xylene, 4 h = 72% = 82% I hydroacylation

26 ydroacylation First hydroacylation precedent (he, 2008) Ts 25 mol% cat. 70 mol% DBU xylene, 4 h = 72% = 82% I Asymmetric intramolecular hydroacylation (Glorius, 2011) 10 mol% cat. 10 mol% DBU dioxane, 80 ºC Ar Cl Ar 28-99%, 96-99% ee Bn s Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983 he, X. Tetrahedron 2008, 64, 8797

27 ydroacylation chanism Concerted but highly asynchronous transition state (Glorius, Grimme) s δ + δ or δ + 2 s s s Conia-ene concerted mechanisms s vs. everse-cope elimination 2 nd 1 st concerted but asynchronous mechanism (Computation) Glorius, F. J. Am. Chem. oc. 2009, 131, Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983

28 Intermolecular ydroacylation Intermolecular hydroacylation of cyclopropenes Cl Ar mol% cat. K 2 C 3 (1 equiv) TF, 40 ºC, 24 h Ar % Ar2 1.6:1 to 20:1 dr Asymmetric intramolecular hydroacylation Ar 1 20 mol% cat. K 3 P 4 (1.5 equiv) TF, 40 ºC, 24 h + 91%, 92% ee Cl (,) Intermolecular hydroacylation of styrenes Ar Ar + 5 mol% cat. K 2 C 3 (1.5 equiv) DM, 40 ºC, 16 h 16-78% Ar Linear tbu + Ar Branched Bn Cl s BF 4 Increased reactivity with Cl 49% yield L:B = > 20:1 C F 3 C 39% yield L:B = < 1:20 Glorius, Angew. Chem., Int. Ed. 2010, 49, Glorius, Angew. Chem., Int. Ed. 2011, 50, Glorius, Angew. Chem., Int. Ed. 2013, 52,

29 Umpolung of Michael Acceptor eck-type cyclization (Fu, 2006): EWG n Br 10 mol% cat. K 3 P 4 (2.5 equiv) glyme, 80 ºC 48-94% EWG n Cl 4 EWG = C 2 Et, C 2 allyl, C 2 (), C n = 1,2 C 2 Et Et Br Et Et Br Et Br tautomerization Fu, J. Am. Chem. oc., 2006, 128,

30 verview Acyl Anions Benzoin condensation tetter reaction ydroacylation omoenolates Annulation Cyclopentene synthesis X Y 2 1 Acylazolium Azolium enolate Claisen rearrangement Cycloaddition Base Catalysis Transesterification Michael addition

31 Generation of omoenolate 1 s s 1 s s 1 s s 1 homoenolate s s

32 Annulation eactions Ar Ar s s Ar 1 2 Ar Ar Ar

33 Cyclopentene ynthesis 1,3,4-trisubstituted Cyclopropene ynthesis by C (air, 2006) mol% cat. 12 mol% DBU TF, T, 8 h 3 Cl 1 2 s s 2 3 Cl Cl Cl 88% yield > 20:1 dr 73% yield > 20:1 dr 55% yield > 20:1 dr air, J. Am. Chem. oc. 2006, 128,

34 chanism 1 s s 2 1 s 3 s 3 - C 2 3 s 1 s s s s s s s

35 Cyclopentene ynthesis Enantioselective ynthesis Cyclopropene by C (Bode, 2007) mol% cat. 12 mol% DBU TF, T, 8 h 2 BF 4 s 2 C 2 1 C 2 Br C 2 C 2 C 2 n Pr C 2 78% yield 11:1 dr 99% ee 93% yield >20:1 dr 98% ee 50% yield 11:1 dr 99% ee 25% yield 14:1 dr 96% ee Bode, J. Am. Chem. oc. 2007, 129,

36 chanism s 1 s 2 1 s 2 C C C s 1 C C s 1 C s 2 C 2

37 chanism rigin of cis/trans stereoselectivity s-cis Cat. C 2 Boat oxy-cope T s-trans Cat. Chair oxy-cope T C 2 s-cis + 10 mol% cat. 15 mol% DBU ClC 2 C 2 Cl 0-23 ºC, 40 h 45% yield > 20:1 dr (72% ee)

38 β-lactam Formation cope of β-lactam formation 2Ar + Ar 1 Ar 2 10 mol% cat. 15 mol% DBU EtAc, 23 ºC, 1 h 45-94% 2 Ar Ar 2 Cl s Ar 1 2 Ar 2 Ar 2 Ar 2 Ar F 3 C 94% yield >20:1 dr 99% ee 45% yield >20:1 dr 98% ee 76% yield 5:1 dr 99% ee 72% yield >20:1 dr 88% ee Bode, J. Am. Chem. oc. 2008, 130,

39 Aza-Benzoin-xy-Cope earrangement chanism 2 Ar s ent-1 s s 2 Ar tautomerization/ Mannich s 2 Ar s 2 Ar 1 s Ar 2

40 verview Acyl Anions Benzoin condensation tetter reaction ydroacylation omoenolates Annulation Cyclopentene synthesis X Y 2 1 Acylazolium Azolium enolate Claisen rearrangement Cycloaddition Base Catalysis Transesterification Michael addition

41 Biomimetic rigin of Acylazolium eactivity Clavulanic acid biosynthesis through acylazolium intermediate 2 P 3 PP- TDP G3P 2 P P acylazolium L-Arg 2 1 C 2 C Clavulanic acid Townsend, J. Am. Chem. oc. 1999, 121,

42 Generation of Acylazolium Genertion of acylazolium intermediate by Mn 2 oxidation (cheidt, 2007) C cat., DBU Mn 2, cheidt, rg. Lett., 2007, 9,

43 Generation of Acylazolium Genertion of acylazolium intermediate by Mn 2 oxidation (cheidt, 2007) C cat., DBU Mn 2, Mn 2 1 s s 1 s s Mn 2 fast 1 s s acylazolium slow 1 s s 1 homoenolate s s cheidt, rg. Lett., 2007, 9,

44 Generation of Acylazolium Ar 1 [] Ar 2 Ar 1 Ar 1 or Ar 1 acylazolium Ar 1 = F, Br comparison of homoenolate/acylazolium reactivity electron donor Ar Ar 1 Y Y =, 1 Y Michael Acceptor Ar Ar 1 1

45 Dihydropyranone ynthesis Through Acylazolium Intramolecular earrangement mol% cat. 20 mol% K t Bu toluene, Δ, 16 h s Cl s 4 3 Intermolecular eaction 1 2 TM + F 20 mol% cat. 40 mol% K t Bu toluene, Δ, 16 h 1 Ar 2 DIPP Cl DIPP Ar Lupton, J. Am. Chem. oc. 2009, 131,

46 chanism acylation addition proton transfer 3 Conjugate addition

47 Enantioselective Coates-Claisen earrangement Catalytic, Enantioselective Couplings with Kojic Acids (Bode, 2010) mol% cat., 40 ºC 2., 23 ºC 78-98% 92-99% ee 2 C 1 2 Cl s 2 C 80% yield 97% ee TB 2 C 95% yield 95% ee TB 2 C Cl TB 87% yield 99% ee 2 C 2 C TB 2 C TB 90% yield 99% ee 98% yield 97% ee 78% yield 99% ee Bode, J. Am. Chem. oc. 2010, 132,

48 2 C s 1 s Claisen earrangement chanism s s 1 1,2-addition 1 s 1 protonation s 1 Breslow intermediate 2 2

49 chanistic Dichotomy Ar + s 1 Y 2 Y =, path B path A 1 2 Y [3,3] Ar Coates-Claisen s 1 Y 2 Ar s choenebeck, Bode (loose ion pair) Mayr, tuder (contact ion pair) Mayr, Angew. Chem., Int. Ed. 2012, 51, choenebeck, Chem. ci. 2012, 3,

50 Enantioselective etero-diels-alder eaction 1 2 Ar mol% cat. DIPEA (1 equiv) /TF 10: % 2 Ar BF 4 s Ar 2 Ar 2 Ar 2 Ar Et 90% yield 99% ee Et 71% yield 99% ee n-pr Et 58% yield 99% ee n-pr 71% yield 99% ee Bode, J. Am. Chem. oc. 2006, 128,

51 Enantioselective etero-diels-alder eaction Transition tate of Azadiene Diels-Alder eaction: 2 Ar Et s Et Ar 2 s 2 Ar Et s C 2 Et s C 2 Et 2 Ar s proton transfer C 2 Et azolium enolate

52 Ketene Cycloaddition Ar 1 + Ar 2 Boc 10 mol% cat. 10 mol% Cs 2 C 3 TF Ar 1 Boc Ar % yield 91-99% ee :1 dr Boc Ar 1 Ar 2 TB Ar 1 Ar 1 Boc Ar 2 Ar 1 azolium enolate Ar 2 Boc Ye,.; rg. Lett. 2008, 10, 277.

53 Ketene Cycloaddition TB Ar [2+2] 1 Ar Ar C 2 Et C 2 Et Ar 1 Ar s Ar azolium enolate Cl [3+2] Ts Ar Ts Cl K Et C 75% yield, 90% ee Bz [4+2] Bz Ar Bz 1. K 2 C 3, /acetone Et 2. mi 2, F- 80% yield, 99% ee Ye,. ynlett 2013, 1614

54 verview Acyl Anions Benzoin condensation tetter reaction ydroacylation omoenolates Annulation Cyclopentene synthesis X Y 2 1 Acylazolium Azolium enolate Claisen rearrangement Cycloaddition Base Catalysis Transesterification Michael addition

55 Transesterification mol% cat. TF, 23 ºC = s or Cy Bn 95% yield 2 96% yield Bn = Et, 85% yield i-pr, 72% yield t-bu, < 1% yield 99% yield favored disfavored olan, rg. Lett. 2002, 4, edrick, rg. Lett. 2002, 4,

56 Kinetic esolution of econdary Alcohols uzuki (2004): Ac 3 3 mol% cat. 3 mol% KtBu TF, 23 ºC 3 Ac % yield 9-58% ee % yield 1-23% ee Maruoka (2005): =, 1-naphthyl 3 mol% cat. 3 mol% KtBu TF, 23 ºC 3 C % yield 84-96% ee % yield 1-23% ee 3 =, 1-naphthyl C 2 C 2 C 2 32% yield 96% ee s = 80 29% yield 94% ee s = 47 27% yield 84% ee s = 16 uzuki, Chem. Commun. 2004, Maruoka, rg. Lett. 2005, 7,

57 Asymmetric Conjugate Addition of 1,3-Dicarbonyls C as non-covalent chiral templates (uang, 2014) 20 mol% cat. 16 mol% LMD + 20 mol% FIP 2 2 4Å M, MTBE - 40 ºC, 48 h 92% yield, 99% ee BF 4 s negative non-linear effects: s 2 s 2 uang, at. Commun. 2014, 5, 3437

58 verview Acyl Anions Benzoin condensation tetter reaction ydroacylation omoenolates Annulation Cyclopentene synthesis X Y 2 1 Acylazolium Azolium enolate Claisen rearrangement Cycloaddition Base Catalysis Transesterification Michael addition

59

60 Application in Total ynthesis ynthesis of (+)-sappanone B reaction type: CF 3 Cl CF 3 C 7.5 mol% cat. Et 3 toluene, 23 ºC, 12 h 92%, 99% ee X X (X = ) (+)-sappanone B (X = ) uzuki, rg. Lett. 2007, 9,

61 Application in Total ynthesis F ynthesis of atorvastatin (Lipitor) reaction type: C + 1:1 E/Z 20 mol% cat. Et 3, 70 ºC 80% F Br Et F C Ca 2+ atorvastatin (Lipitor) tbu 2. Cl,, then a 3. Ca(Ac) 2 Paal-Knorr eaction oth, Tetrahedron Lett. 1992, 33,

62 Application in Total ynthesis ynthesis of maremycin B reaction type: BF 4 s + 5 mol% cat. DBU, TF, 23 ºC 76%, 5:1 dr C 78% ee 99% ee after 1 recrystalization 5 steps maremycin B cheidt, Angew. Chem. Int. Ed. 2012, 51,

63 Application in Total ynthesis ynthesis of ( )-7-deoxyloganin reaction type: C 2 C 2 C 2 20 mol% cat. TF, -78ºC-23 ºC 63%, 3.4:1 dr, 97% ee 4 steps ( )-7-deoxyloganin Candish, Lupton, rg. Lett. 2010, 12,

64 Application in Total ynthesis ynthesis of (+)-Dactylolide reaction type: TBDP C TB tbu I (30 mol%) tbu TBDP C TB 11 steps tbu tbu DBU, DMAP, 4Å M C 2 Cl 2, 25 ºC, 20 h 65% 4 steps (+)-dactylolide ong, Angew. Chem. Int. Ed. 2012, 51,

65 eviews 1. -eterocyclic Carbenes as rganocatalysts olan, Angew. Chem. Int. Ed. 2007, 46, rganocatalysis by -eterocyclic Carbenes Enders, Chem. ev. 2007, 107, A Continuum of Progress: Applications of -etereocyclic Carbene Catalysis in Total ynthesis heidt, Angew. Chem. Int. Ed. 2012, 51, rganocatalytic eactions Enabled by eterocyclic Carbenes ovis, Chem. ev. 2015, 115,